Lysyl Oxidase-Like 1 (LOXL1) Up-Regulation in Chondrocytes Promotes M1 Macrophage Activation in Osteoarthritis via NF-κB and STAT3 Signaling.

IF 6.2 Q1 IMMUNOLOGY
ImmunoTargets and Therapy Pub Date : 2025-03-24 eCollection Date: 2025-01-01 DOI:10.2147/ITT.S512768
Yuyun Jiang, Shang Wang, Wei Zhu, Xi Liu, Yanwei Yang, Liyue Huo, Jixian Ye, Yongbin Ma, Yuepeng Zhou, Zhe Yang, Jiahui Mao, Xuefeng Wang
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引用次数: 0

Abstract

Purpose: Osteoarthritis (OA) constitutes a widespread degenerative joint disease predominantly affecting the elderly, leading to disability. There is still a lack of biomarkers for OA, so it cannot be intervened in time.

Methods: OA biomarkers were identified from human cartilage datasets using LASSO and SVM-RFE, followed by ROC analysis. LOXL1 was prioritized for further research due to its high expression in OA cartilage and robust predictive performance. Anterior cruciate ligament transection (ACLT) surgery-induced OA rats were used to explore the correlation between LOXL1 and inflammatory factors and macrophages. Macrophage markers and cytokine secretion were detected from macrophages treated with LOXL1, or co-cultured with chondrocytes after LOXL1 siRNA silencing.

Results: Five hub biomarkers with OA-specific expression were identified. Elevated LOXL1 correlated with IL-6 and IL-8 in patients and increased M1 macrophages in OA rats. LOXL1-stimulated macrophages upregulated CD86 and inflammatory cytokines. Silencing LOXL1 in chondrocytes reduced CD86, inflammatory cytokines, and NF-κB p65 and p-STAT3 expression in co-cultured macrophages, mitigating MMP13 and chondrocyte apoptosis. STAT3 and NF-κB signal inhibition reduces p-STAT3, p-p65, CD86, IL-6 and IL-1β expression in LOXL1-stimulated macrophages.

Conclusion: This study underscores the pivotal role of LOXL1 in activating M1 macrophages through NF-κB and STAT3 signaling, thereby promoting pro-inflammatory cytokine secretion and contributing to OA pathogenesis. LOXL1 holds promise as a potential marker for early diagnosis of OA inflammation and as a novel therapeutic target.

软骨细胞中赖氨酸氧化酶样1 (LOXL1)上调通过NF-κB和STAT3信号通路促进骨关节炎M1巨噬细胞活化。
目的:骨关节炎(OA)是一种广泛存在的退行性关节疾病,主要影响老年人,导致残疾。目前仍缺乏OA的生物标志物,因此无法及时干预。方法:使用LASSO和SVM-RFE从人软骨数据集中识别OA生物标志物,然后进行ROC分析。由于其在OA软骨中的高表达和强大的预测性能,LOXL1被优先考虑进一步研究。采用前交叉韧带横断(ACLT)手术诱导的OA大鼠,探讨LOXL1与炎症因子和巨噬细胞的相关性。用LOXL1处理巨噬细胞,或在LOXL1 siRNA沉默后与软骨细胞共培养巨噬细胞,检测巨噬细胞标志物和细胞因子分泌。结果:鉴定出5个具有oa特异性表达的枢纽生物标志物。LOXL1升高与患者IL-6、IL-8及OA大鼠M1巨噬细胞增加相关。loxl1刺激的巨噬细胞上调CD86和炎症细胞因子。沉默软骨细胞LOXL1可降低共培养巨噬细胞中CD86、炎症因子、NF-κB p65和p-STAT3的表达,减轻MMP13和软骨细胞凋亡。STAT3和NF-κB信号抑制可降低loxl1刺激的巨噬细胞中p-STAT3、p-p65、CD86、IL-6和IL-1β的表达。结论:本研究强调了LOXL1通过NF-κB和STAT3信号通路激活M1巨噬细胞,从而促进促炎细胞因子分泌,参与OA发病的关键作用。LOXL1有望成为OA炎症早期诊断的潜在标志物和新的治疗靶点。
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来源期刊
CiteScore
16.50
自引率
0.00%
发文量
7
审稿时长
16 weeks
期刊介绍: Immuno Targets and Therapy is an international, peer-reviewed open access journal focusing on the immunological basis of diseases, potential targets for immune based therapy and treatment protocols employed to improve patient management. Basic immunology and physiology of the immune system in health, and disease will be also covered.In addition, the journal will focus on the impact of management programs and new therapeutic agents and protocols on patient perspectives such as quality of life, adherence and satisfaction.
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